PROJECT SUMMARY: The primary goal of our research is to mechanistically characterize systemic immunosuppression induced by ultraviolet B radiation (UVB). The immunosuppressive effects of UVB are involved in the ability of this environmental stimulus to induce skin cancers. Moreover, UVB radiation treatments are used clinically to treat inflammatory skin disorders, in great part to its immunosuppressive effects. The planned research plans to take advantage of results of previous studies both in our laboratory and others indicating that UVB-mediated systemic immunosuppression involves novel glycerophosphocholine-derived lipids produced by epidermal cells in response to UVB. These compounds, some of which have not been structurally characterized, act as agonists for the Platelet-activating Factor (PAF) receptor. Accumulating evidence suggests that these PAF-R agonists exert immunosuppressive effects via a complex interplay of cell types and cytokines including mast cells, cyclooxygenase-2-produced eicosanoids, interleukin-10 and histamine. Two specific aims are planned to mechanistically characterize the complex pathway of UVB-mediated systemic immunosuppression using a well-established murine model of contact hypersensitivity. The first aim will use mass spectrometry to structurally characterize and quantitate PAF-R agonists produced by UVB in murine skin. The amounts of these novel PAF-R ligands produced enzymatically as well as through non- enzymatic free radical-mediated oxidation of glycerophosphosphocholines will be assessed using a mouse defective in PAF enzymatic synthesis and use of systemic antioxidants. The second aim will characterize the roles of mast cells and regulatory T cells using novel murine transplantation studies. Completion of the planned studies to characterize the cell types and mediators involved in UVB-mediated systemic immunosuppression should result in an enhanced understanding of this important process intimately involved in skin cancer.